Reduced Susceptibility to Two-Stage Skin Carcinogenesis in Mice with Epidermis-Specific Deletion of Cd151

Altered expression of the tetraspanin CD151 is associated with skin tumorigenesis; however, whether CD151 is causally involved in the tumorigenic process is not known. To evaluate its role in tumor formation, we subjected epidermis-specific Cd151 knockout mice to chemical skin carcinogenesis. Mice lacking epidermal Cd151 developed fewer and smaller tumors than wild-type mice after treatment with 7,12-dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA). Furthermore, Cd151-null epidermis showed a reduced hyperproliferative response to short-term treatment with TPA as compared with wild-type skin, whereas epidermal turnover was increased. Tumors were formed in equal numbers after DMBA-only treatment. We suggest that DMBA-initiated keratinocytes lacking Cd151 leave their niches in the epidermis and hair follicles in response to TPA treatment and subsequently are lost by differentiation. Because genetic ablation of Itga3 also reduced skin tumor formation, we tested whether reduced expression of α3 could further suppress tumor formation in epidermis-specific Cd151 knockout mice. Although DMBA/TPA-induced formation of skin tumors was similar in compound heterozygotes for Cd151 and Itga3 to that in wild-type mice, heterozygosity for Itga3 on a Cd151-null background diminished tumorigenesis, suggesting genetic interaction between the two genes. We thus identify CD151 as a critical factor in TPA-dependent skin carcinogenesis

Identification of TRPC6 as a possible candidate target gene within an amplicon at 11q21-q22.2 for migratory capacity in head and neck squamous cell carcinomas

Abstract: Background: Cytogenetic and gene expression analyses in head and neck squamous cell carcinomas (HNSCC) have allowed identification of genomic aberrations that may contribute to cancer pathophysiology. Nevertheless, the molecular consequences of numerous genetic alterations still remain unclear. Methods: To identify novel genes implicated in HNSCC pathogenesis, we analyzed the genomic alterations present in five HNSCC-derived cell lines by array CGH, and compared high level focal gene amplifications with gene expression levels to identify genes whose expression is directly impacted by these genetic events. Next, we knocked down TRPC6, one of the most highly amplified and over-expressed genes, to characterize the biological roles of TRPC6 in carcinogenesis. Finally, real time PCR was performed to determine TRPC6 gene dosage and mRNA levels in normal mucosa and human HNSCC tissues. Results: The data showed that the HNSCC-derived cell lines carry most of the recurrent genomic abnormalities previously described in primary tumors. High-level genomic amplifications were found at four chromosomal sites (11q21-q22.2, 18p11.31-p11.21, 19p13.2-p13.13, and 21q11) with associated gene expression changes in selective candidate genes suggesting that they may play an important role in the malignant behavior of HNSCC. One of the most dramatic alterations of gene transcription involved the TRPC6 gene (located at 11q21-q22.2) which has been recently implicated in tumour invasiveness. siRNA-induced knockdown of TRPC6 expression in HNSCC-derived cells dramatically inhibited HNSCC-cell invasion but did not significantly alter cell proliferation. Importantly, amplification and concomitant overexpression of TRPC6 was also found in HNSCC tumour samples. Conclusions: Altogether, these data show that TRPC6 is likely to be a target for 11q21-22.2 amplification that confers enhanced invasive behavior to HNSCC cells. Therefore, TRPC6 may be a promising therapeutic target in the treatment of HNSCC.This work was supported by Instituto de Salud Carlos III-Fondo de Investigacion Sanitaria [FIS PI11/929 to M.-D.C and C. S.]; Red Tematica de Investigacion Cooperativa en Cancer [RD12/0036/0015] Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness & European Regional Development Fund (ERDF); and Obra Social CajAstur-Instituto Universitario de Oncologia del Principado de Asturias.Bernaldo De Quirós, S.; Merlo, A.; Secades, P.; Zambrano, I.; Saenz De Santa María, I.; Ugidos, N.; Jantus Lewintre, E.... (2013). Identification of TRPC6 as a possible candidate target gene within an amplicon at 11q21-q22.2 for migratory capacity in head and neck squamous cell carcinomas. BMC Cancer. 13(116):1-9. https://doi.org/10.1186/1471-2407-13-116S1913116Akervall J: Genomic screening of head and neck cancer and its implications for therapy planning. Eur Arch Otorhinolaryngol. 2006, 263: 297-304. 10.1007/s00405-006-1039-1.Squire JA, Bayani J, Luk C, Unwin L, Tokunaga J, MacMillan C, Irish J, Brown D, Gullane P, Kamel-Reid S: Molecular cytogenetic analysis of head and neck squamous cell carcinoma: by comparative genomic hybridization, spectral karyotyping, and expression array analysis. Head Neck. 2002, 24: 874-887. 10.1002/hed.10122.Perez-Ordonez B, Beauchemin M, Jordan RC: Molecular biology of squamous cell carcinoma of the head and neck. J Clin Pathol. 2006, 59: 445-453. 10.1136/jcp.2003.007641.Tan KD, Zhu Y, Tan HK, Rajasegaran V, Aggarwal A, Wu J, Wu HY, Hwang J, Lim DT, Soo KC, Tan P: Amplification and overexpression of PPFIA1, a putative 11q13 invasion suppressor gene, in head and neck squamous cell carcinoma. Genes Chromosomes Cancer. 2008, 47: 353-362. 10.1002/gcc.20539.Rodrigo JP, Garcia LA, Ramos S, Lazo PS, Suarez C: EMS1 Gene amplification correlates with poor prognosis in squamous cell carcinomas of the head and neck. Clin Cancer Res. 2000, 6: 3177-3182.Callender T, el-Naggar AK, Lee MS, Frankenthaler R, Luna MA, Batsakis JG: PRAD-1 (CCND1)/cyclin D1 oncogene amplification in primary head and neck squamous cell carcinoma. Cancer. 1994, 74: 152-158. 10.1002/1097-0142(19940701)74:13.0.CO;2-K.Huang X, Gollin SM, Raja S, Godfrey TE: High-resolution mapping of the 11q13 amplicon and identification of a gene, TAOS1, that is amplified and overexpressed in oral cancer cells. Proc Natl Acad Sci U S A. 2002, 99: 11369-11374. 10.1073/pnas.172285799.Gorogh T, Weise JB, Holtmeier C, Rudolph P, Hedderich J, Gottschlich S, Hoffmann M, Ambrosch P, Csiszar K: Selective upregulation and amplification of the lysyl oxidase like-4 (LOXL4) gene in head and neck squamous cell carcinoma. J Pathol. 2007, 212: 74-82. 10.1002/path.2137.Begum A, Imoto I, Kozaki K, Tsuda H, Suzuki E, Amagasa T, Inazawa J: Identification of PAK4 as a putative target gene for amplification within 19q13.12-q13.2 In oral squamous-cell carcinoma. Cancer Sci. 2009, 100: 1908-1916. 10.1111/j.1349-7006.2009.01252.x.Secades P, Rodrigo JP, Hermsen M, Alvarez C, Suarez C, Chiara MD: Increase in gene dosage is a mechanism of HIF-1alpha constitutive expression in head and neck squamous cell carcinomas. Genes Chromosomes Cancer. 2009, 48: 441-454. 10.1002/gcc.20652.Singh B, Gogineni SK, Sacks PG, Shaha AR, Shah JP, Stoffel A, Rao PH: Molecular cytogenetic characterization of head and neck squamous cell carcinoma and refinement of 3q amplification. Cancer Res. 2001, 61: 4506-4513.Baldwin C, Garnis C, Zhang L, Rosin MP, Lam WL: Multiple microalterations detected at high frequency in oral cancer. Cancer Res. 2005, 65: 7561-7567.Roman E, Meza-Zepeda LA, Kresse SH, Myklebost O, Vasstrand EN, Ibrahim SO: Chromosomal aberrations in head and neck squamous cell carcinomas in Norwegian and Sudanese populations by array comparative genomic hybridization. Oncol Rep. 2008, 20: 825-843.Weber RG, Sommer C, Albert FK, Kiessling M, Cremer T: Clinically distinct subgroups of glioblastoma multiforme studied by comparative genomic hybridization. Lab Invest. 1996, 74: 108-119.Knuutila S, Bjorkqvist AM, Autio K, Tarkkanen M, Wolf M, Monni O, Szymanska J, Larramendy ML, Tapper J, Pere H: DNA copy number amplifications in human neoplasms: review of comparative genomic hybridization studies. Am J Pathol. 1998, 152: 1107-1123.Menghi-Sartorio S, Mandahl N, Mertens F, Picci P, Knuutila S: DNA copy number amplifications in sarcomas with homogeneously staining regions and double minutes. Cytometry. 2001, 46: 79-84. 10.1002/cyto.1068.Imoto I, Tsuda H, Hirasawa A, Miura M, Sakamoto M, Hirohashi S, Inazawa J: Expression of cIAP1, a target for 11q22 amplification, correlates with resistance of cervical cancers to radiotherapy. Cancer Res. 2002, 62: 4860-4866.Dai Z, Zhu WG, Morrison CD, Brena RM, Smiraglia DJ, Raval A, Wu YZ, Rush LJ, Ross P, Molina JR: A comprehensive search for DNA amplification in lung cancer identifies inhibitors of apoptosis cIAP1 and cIAP2 as candidate oncogenes. Hum Mol Genet. 2003, 12: 791-801. 10.1093/hmg/ddg083.Bashyam MD, Bair R, Kim YH, Wang P, Hernandez-Boussard T, Karikari CA, Tibshirani R, Maitra A, Pollack JR: Array-based comparative genomic hybridization identifies localized DNA amplifications and homozygous deletions in pancreatic cancer. Neoplasia. 2005, 7: 556-562. 10.1593/neo.04586.Helias-Rodzewicz Z, Perot G, Chibon F, Ferreira C, Lagarde P, Terrier P, Coindre JM, Aurias A: YAP1 And VGLL3, encoding two cofactors of TEAD transcription factors, are amplified and overexpressed in a subset of soft tissue sarcomas. Genes Chromosomes Cancer. 2010, 49: 1161-1171. 10.1002/gcc.20825.Fernandez LA, Northcott PA, Dalton J, Fraga C, Ellison D, Angers S, Taylor MD, Kenney AM: YAP1 Is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates sonic hedgehog-driven neural precursor proliferation. Genes Dev. 2009, 23: 2729-2741. 10.1101/gad.1824509.Muramatsu T, Imoto I, Matsui T, Kozaki K, Haruki S, Sudol M, Shimada Y, Tsuda H, Kawano T, Inazawa J: YAP is a candidate oncogene for esophageal squamous cell carcinoma. Carcinogenesis. 2010, 32: 389-398.Chigurupati S, Venkataraman R, Barrera D, Naganathan A, Madan M, Paul L, Pattisapu JV, Kyriazis GA, Sugaya K, Bushnev S: Receptor channel TRPC6 is a key mediator of notch-driven glioblastoma growth and invasiveness. Cancer Res. 2010, 70: 418-427. 10.1158/0008-5472.CAN-09-2654.Ding X, He Z, Zhou K, Cheng J, Yao H, Lu D, Cai R, Jin Y, Dong B, Xu Y, Wang Y: Essential role of TRPC6 channels in G2/M phase transition and development of human glioma. J Natl Cancer Inst. 2010, 102: 1052-1068. 10.1093/jnci/djq217.Lansford CDGR, Bier H: Head and neck cancers. 1999, Dordrecht: Kluwer Academic Pressvan den Ijssel P, Tijssen M, Chin SF, Eijk P, Carvalho B, Hopmans E, Holstege H, Bangarusamy DK, Jonkers J, Meijer GA: Human and mouse oligonucleotide-based array CGH. Nucleic Acids Res. 2005, 33: e192-10.1093/nar/gni191.Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−delta delta C(T)) method. Methods. 2001, 25: 402-408. 10.1006/meth.2001.1262.Gollin SM: Chromosomal alterations in squamous cell carcinomas of the head and neck: window to the biology of disease. Head Neck. 2001, 23: 238-253. 10.1002/1097-0347(200103)23:33.0.CO;2-H.Smeets SJ, Braakhuis BJ, Abbas S, Snijders PJ, Ylstra B, van de Wiel MA, Meijer GA, Leemans CR, Brakenhoff RH: Genome-wide DNA copy number alterations in head and neck squamous cell carcinomas with or without oncogene-expressing human papillomavirus. Oncogene. 2006, 25: 2558-2564. 10.1038/sj.onc.1209275.Snijders AM, Schmidt BL, Fridlyand J, Dekker N, Pinkel D, Jordan RC, Albertson DG: Rare amplicons implicate frequent deregulation of cell fate specification pathways in oral squamous cell carcinoma. Oncogene. 2005, 24: 4232-4242. 10.1038/sj.onc.1208601.Canel M, Secades P, Garzon-Arango M, Allonca E, Suarez C, Serrels A, Frame M, Brunton V, Chiara MD: Involvement of focal adhesion kinase in cellular invasion of head and neck squamous cell carcinomas via regulation of MMP-2 expression. Br J Cancer. 2008, 98: 1274-1284. 10.1038/sj.bjc.6604286.Canel M, Secades P, Rodrigo JP, Cabanillas R, Herrero A, Suarez C, Chiara MD: Overexpression of focal adhesion kinase in head and neck squamous cell carcinoma is independent of fak gene copy number. Clin Cancer Res. 2006, 12: 3272-3279. 10.1158/1078-0432.CCR-05-1583.Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T, Clark L, Bayani N, Coppe JP, Tong F: A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell. 2006, 10: 515-527. 10.1016/j.ccr.2006.10.008.Jarvinen AK, Autio R, Kilpinen S, Saarela M, Leivo I, Grenman R, Makitie AA, Monni O: High-resolution copy number and gene expression microarray analyses of head and neck squamous cell carcinoma cell lines of tongue and larynx. Genes Chromosomes Cancer. 2008, 47: 500-509. 10.1002/gcc.20551.Lockwood WW, Chari R, Coe BP, Girard L, Macaulay C, Lam S, Gazdar AF, Minna JD, Lam WL: DNA amplification is a ubiquitous mechanism of oncogene activation in lung and other cancers. Oncogene. 2008, 27: 4615-4624. 10.1038/onc.2008.98.Weber A, Hengge UR, Stricker I, Tischoff I, Markwart A, Anhalt K, Dietz A, Wittekind C, Tannapfel A: Protein microarrays for the detection of biomarkers in head and neck squamous cell carcinomas. Hum Pathol. 2007, 38: 228-238. 10.1016/j.humpath.2006.07.012.Pacheco MM, Kowalski LP, Nishimoto IN, Brentani MM: Differential expression of c-jun and c-fos mRNAs in squamous cell carcinoma of the head and neck: associations with uPA, gelatinase B, and matrilysin mRNAs. Head Neck. 2002, 24: 24-32. 10.1002/hed.10009.Xie M, Sun Y, Li Y: Expression of matrix metalloproteinases in supraglottic carcinoma and its clinical implication for estimating lymph node metastases. Laryngoscope. 2004, 114: 2243-2248. 10.1097/01.mlg.0000149467.18822.59.Werner JA, Rathcke IO, Mandic R: The role of matrix metalloproteinases in squamous cell carcinomas of the head and neck. Clin Exp Metastasis. 2002, 19: 275-282. 10.1023/A:1015531319087.Zhang L, Ye DX, Pan HY, Wei KJ, Wang LZ, Wang XD, Shen GF, Zhang ZY: Yes-associated protein promotes cell proliferation by activating Fos related activator-1 in oral squamous cell carcinoma. Oral Oncol. 2011, 47: 693-697. 10.1016/j.oraloncology.2011.06.003.Yokoyama T, Osada H, Murakami H, Tatematsu Y, Taniguchi T, Kondo Y, Yatabe Y, Hasegawa Y, Shimokata K, Horio Y: YAP1 Is involved in mesothelioma development and negatively regulated by Merlin through phosphorylation. Carcinogenesis. 2008, 29: 2139-2146. 10.1093/carcin/bgn200.Diep CH, Zucker KM, Hostetter G, Watanabe A, Hu C, Munoz RM, Von Hoff DD, Han H: Down-regulation of Yes associated protein 1 expression reduces cell proliferation and clonogenicity of pancreatic cancer cells. PLoS One. 7: e32783-Kang W, Tong JH, Chan AW, Lee TL, Lung RW, Leung PP, So KK, Wu K, Fan D, Yu J: Yes-associated protein 1 exhibits oncogenic property in gastric cancer and its nuclear accumulation associates with poor prognosis. Clin Cancer Res. 2011, 17: 2130-2139. 10.1158/1078-0432.CCR-10-2467.Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC, Deng CX, Brugge JS, Haber DA: Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci U S A. 2006, 103: 12405-12410. 10.1073/pnas.0605579103.Guilbert A, Dhennin-Duthille I, Hiani YE, Haren N, Khorsi H, Sevestre H, Ahidouch A, Ouadid-Ahidouch H: Expression of TRPC6 channels in human epithelial breast cancer cells. BMC Cancer. 2008, 8: 125-10.1186/1471-2407-8-125.Yue D, Wang Y, Xiao JY, Wang P, Ren CS: Expression of TRPC6 in benign and malignant human prostate tissues. Asian J Androl. 2009, 11: 541-547. 10.1038/aja.2009.53.Cai R, Ding X, Zhou K, Shi Y, Ge R, Ren G, Jin Y, Wang Y: Blockade of TRPC6 channels induced G2/M phase arrest and suppressed growth in human gastric cancer cells. Int J Cancer. 2009, 125: 2281-2287. 10.1002/ijc.24551.Shi Y, Ding X, He ZH, Zhou KC, Wang Q, Wang YZ: Critical role of TRPC6 channels in G2 phase transition and the development of human oesophageal cancer. Gut. 2009, 58: 1443-1450. 10.1136/gut.2009.181735.Thebault S, Flourakis M, Vanoverberghe K, Vandermoere F, Roudbaraki M, Lehen’kyi V, Slomianny C, Beck B, Mariot P, Bonnal JL: Differential role of transient receptor potential channels in Ca2+ entry and proliferation of prostate cancer epithelial cells. Cancer Res. 2006, 66: 2038-2047. 10.1158/0008-5472.CAN-05-0376.El Boustany C, Bidaux G, Enfissi A, Delcourt P, Prevarskaya N, Capiod T: Capacitative calcium entry and transient receptor potential canonical 6 expression control human hepatoma cell proliferation. Hepatology. 2008, 47: 2068-2077. 10.1002/hep.22263

Financiación para publicar en acceso abierto : el acuerdo transformativo CRUE-CSIC con Elsevier

Aquesta presentació tracta sobre els models de publicació en accés obert amb Elsevier: cobertura de les APCs (revistes gold i híbrides); presentació de l'eina EOAP (Elsevier Open Access Publishing): una guia pels autors; publicació de capítols de llibre en accés obert i els objectius de desenvolupament sostenible a Scopus: accés i anàlisi posant el focus en "Climate action", amb la UAB com a exemple

Active battery cell equalization using a Flyback converter with current mode control

International Conference on Power Electronics (CIEP) (14th, 2018, Cholula, Mexico

Actividad investigadora de los residentes de medicina interna de Galicia

Aim: To know the research activity of the residents of internal medicine (MI) of Galicia. Method: a questionnaire was sent to the residents (MIR) of internal medicine of Galicia in May 2011. Variables analyzed were: congress presentations, scientific papers, book chapters, degree in advanced studies, doctoral thesis and participation in financed projects of investigation. Results were classified according to the year of residence training. Results : 39 MIR answered the questionnaire (68% of the MIR of MI of Galicia): 9 first year MIR, 14 MIR 2º, 6 MIR 3º, 6 MIR 4º and 4 MIR 5º. The mean of presentations to autonomic congresses per resident was 5.85 (DS 5.22), 2,51 (3.64) to national congresses and 0,74 (1,9) to internationals. 41% and 87,2% had not participated in any presentation neither in national nor in international congresses, respectively. 29 scientific papers were registered, with the mean under 1 paper per resident. 71,8% did not have any paper. 15% were undertaking the degree in advanced studies. No differences were found regarding the research activity according to the years of residence training. No differences were found according to the belonging of the MIR to university hospitals. Conclusion: The research activity of the residents of Galicia is deficient. It is necessary to achieve a better implication from residents, tutors and hospital teaching units and to implant the measures to change this situation. We must stimulate activities of research education and promotion of investigation in the hospitals of Galicia.OBJETIVO: Conocer la actividad investigadora de los residentes de medicina interna (MI) de Galicia. MÉTODO: encuesta remitida a los residentes (MIR) de Medicina Interna de Galicia en Mayo de 2011. Las variables analizadas fueron: comunicaciones a congresos, publicaciones en revistas, capítulos de libros, Diploma de Estudios Avanzados (DEA), tesis doctoral y participación en proyectos de investigación financiados. Los resultados se clasificaron según el año de esidencia. Resultados : participaron 39 residentes (68% de los MIR de MI de Galicia): 9 MIR de 1º año, 14 MIR 2º, 6 MIR 3º, 6 MIR 4º y 4 MIR 5º. Se registró una media de comunicaciones a congresos autonómicos por residente de 5,.85 (DS 5.22), 2,51 (3.64) a congresos nacionales y 0,74 (1,9) a internacionales. El 41% y el 87,2% no había participado en ninguna comunicación a congresos nacionales e internacionales, respectivamente. Se registraron un total de 29 publicaciones, con una media inferior a 1 publicación por residente. El 71,8% no había participado en ninguna publicación. El 15% estaba realizando o habían obtenido el DEA. No se observaron diferencias en la actividad investigadora en relación al avance en los años de residencia. Tampoco se observaron diferencias en cuanto a si los residentes procedían o no de hospitales universitarios. Conclusión: la actividad investigadora de los residentes de medicina interna de Galicia es deficiente. Es preciso conseguir una mayor implicación por parte de los residentes, tutores y unidades de docencia de los distintos hospitales y acometer las medidas necesarias para cambiar esta situación, estimulando actividades de formación y promoción de la investigación en los hospitales de Galicia